Epidemiologists estimate that 25% of human AIDS patients use injectable opiates, making drug abuse a major contributory variable in the AIDS epidemic. One hypothesis for the increased rate of AIDS among street opiate addicts, compared to the general population, proposes that the immunomodulatory properties of opiates make immune systems of addicts vulnerable to infectious agents such as HIV and those which complicate the condition known as AIDS. Findings that peripheral T lymphocytes have specific opiate binding sites support the hypothesis that opiates themselves are a direct factor in modulating immunocompetence in addicts. However, before the etiology of opiate-induced immunomodulation can be fully understood, a fundamental need exists to determine the opiate specificity and ionic requirements of the opiate-ligand/binding site(s) interactions of the T lymphocyte. Second, alcohol and cocaine alters the immunomodulatory properties of opiates, and it would therefore be instructive to study how these drugs affect opiate binding to lymphocytes because of the relevance of such polydrug interactions to the circumstances of street addiction. Third, by studying the difference in variance in Bmax (the number of binding sites per lymphocyte) between pairs of monozygotic twins compared to dizygotic twins, the contribution of heredity to a critical component of opiate-induced immunomodulation can also be assessed. Fourth, measurement of opiate binding to lymphocytes from street addicts would test whether the lymphocytes demonstrate tolerance for opiates. Finally, lymphocyte-opiate interactions can be exploited to evaluate the modulation of secondary biochemical signals (Ca+2 influx and cAMP concentration) which control cellular metabolism and ultimately immune function. It is only by careful mechanistic studies of the binding of opiates to lymphocytes that the apparent immunodeficiency of street addicts can be addressed and their susceptibility to AIDS and other infectious diseases interpreted. With knowledge of the etiology of opiate immunomodulation, it may be possible to devise intervention strategies to effectively reverse the immunodeficiency and AIDS-susceptibility of the street opiate addict.